OBJECTIVE

To evaluate the risk factors for postextubation laryngeal stridor and its prevention by hydrocortisone in adult patients.

METHODS

Prospective, randomized, double-blind, placebo controlled study.

METHODS

Medical and surgical ICU of a tertiary teaching hospital.

METHODS

77 consecutive patients of both sexes, who had undergone tracheal intubation for more than 24 h and fulfilled the weaning criteria, were eligible for the study. Patients were excluded if they were less than 15 years of age, had a disease or the surgery of the throat, or had been extubated during the current hospitalization.

METHODS

The control group received placebo (normal saline 3 cc) and the experimental group received hydrocortisone 100 mg by intravenous infusion 60 min before extubation.

METHODS

Patients were observed 24 h after extubation for symptoms or signs of laryngeal edema or stridor: prolonged inspiration with accessory usage of respiratory muscles or crowing sound with inspiration or reintubation.

RESULTS

The overall incidence of postextubation stridor was 22% (17/77). Only one patient (1%), who belonged to the control group, needed reintubation. 39% of female patients and 17% of male patients developed stridor. The relative risk of females developing this complication was 2.29. 7/39 of the hydrocortisone group and 10/38 of patients in the control group developed postextubation stridor.

CONCLUSIONS

Hydrocortisone did not significantly reduce the incidence of postextubation laryngeal edema or stridor. From the risk factors evaluated, we were unable to demonstrate a statistical correlation between postextubation stidor and the duration of the intubation, the patient's age, the internal diameter of the endotracheal tube, or the route of intubation. However, female patients were more likely to develop this complication.

Ultra Performance Liquid Chromatography (UPLC) is a relatively new technique giving new possibilities in liquid chromatography, especially concerning decrease of time and solvent consumption. UPLC chromatographic system is designed in a special way to withstand high system back-pressures. Special analytical columns UPLC Acquity UPLC BEH C(18) packed with 1.7 microm particles are used in connection with this system. The quality control analyses of four pharmaceutical formulations were transferred from HPLC to UPLC system. The results are compared for Triamcinolon cream containing trimacinolone acetonide, methylparaben, propylparaben and triamcinolone as degradation product, for Hydrocortison cream (hydrocortisone acetate, methylparaben, propylparaben and hydrocortisone degradation product), for Indomethacin gel (indomethacin and its degradation products 4-chlorobenzoic acid and 5-methoxy-2-methylindoleacetic acid) and for Estrogel gel (estradiol, methylparaben, propylparaben and estrone as degradation product). The UPLC system allows shortening analysis time up to nine times comparing to the conventional system using 5 microm particle packed analytical columns. In comparison with 3 microm particle packed analytical columns analysis should be shortened about three times. The negative effect of particle decrease is back-pressure increase about nine times (versus 5 microm) or three times (versus 3 microm), respectively. The separation on UPLC is performed under very high pressures (up to 100MPa is possible in UPLC system), but it has no negative influence on analytical column or other components of chromatographic system. Separation efficiency remains maintained or is even improved. Differences and SST parameters, advantages and disadvantages of UPLC are discussed.

The time course of the effects of an acute elevation in morning plasma cortisol on the daytime profiles of plasma glucose, serum insulin, and insulin secretion under constant glucose infusion was determined using a placebo-controlled design in two groups of eight normal men. In one group, the elevation of plasma cortisol was obtained by oral administration of 100 mg hydrocortisone. In the other group, the elevation was obtained by intravenous administration of 25 micrograms of corticotropin-releasing hormone. In both studies, the immediate effect of the increase in plasma cortisol, even when of very small amplitude, was an abrupt inhibition of insulin secretion without change in glucose concentration. Larger cortisol elevations, such as occurred after hydrocortisone administration, were additionally associated with the appearance of insulin resistance, which developed 4-6 h after the cortisol elevation and persisted for>> 16 h. These observations support the concept that the 24-h cortisol rhythmicity is responsible, at least in part, for the normal diurnal variation in glucose tolerance.

The Children's Cancer Group (CCG) 1952 clinical trial for children with standard-risk acute lymphoblastic leukemia (SR-ALL) compared intrathecal (IT) methotrexate (MTX) with IT triples (ITT) (MTX, cytarabine, and hydrocortisone sodium succinate [HSS]) as presymptomatic central nervous system (CNS) treatment. Following remission induction, 1018 patients were randomized to receive IT MTX and 1009 ITT. Multivariate analysis identified male sex, hepatomegaly, CNS-2 status, and age younger than 2 or older than 6 years as significant predictors of isolated CNS (iCNS) relapse. The 6-year cumulative incidence estimates of iCNS relapse are 3.4% +/- 1.0% for ITT and 5.9% +/- 1.2% for IT MTX; P = .004. Significantly more relapses occurred in bone marrow (BM) and testicles with ITT than IT MTX, particularly among patients with T-cell phenotype or day 14 BM aspirate containing 5% to 25% blasts. Thus, the estimated 6-year event-free survivals (EFS) with ITT or IT MTX are equivalent at 80.7% +/- 1.9% and 82.5% +/- 1.8%, respectively (P = .3). Because the salvage rate after BM relapse is inferior to that after CNS relapse, the 6-year overall survival (OS) for ITT is 90.3% +/- 1.5% versus 94.4% +/- 1.1% for IT MTX (P = .01). It appears that ITT improves presymptomatic CNS treatment but does not improve overall outcome.

OBJECTIVE

We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy.

METHODS

Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 [DOSAGE ERROR CORRECTED] Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission.

RESULTS

Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report.

CONCLUSIONS

This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.

Importance: The combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.

Objective: To determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.

Design, setting, and participants: Randomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.

Interventions: Patients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102).

Main outcomes and measures: The primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses.

Results: Among 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively).

Conclusions and relevance: In patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.

Trial registration: ClinicalTrials.gov Identifier: NCT03389555.

BACKGROUND

Vehicle-controlled studies have demonstrated the efficacy and safety of tacrolimus ointment for patients with atopic dermatitis.

OBJECTIVE

This study was undertaken to compare 0.03% and 0.1% tacrolimus ointment with 0.1% hydrocortisone-17-butyrate ointment, a midpotent to potent topical corticosteroid, in the treatment of adult patients with moderate-to-severe atopic dermatitis.

METHODS

Patients applied ointment twice daily to all affected areas for 3 weeks in this multicenter, randomized, double-blind, parallel-group study. The primary endpoint was the modified eczema area and severity index (mEASI) mean area under the curve as a percentage of baseline.

RESULTS

Five hundred seventy patients were randomized and received treatment. Discontinuations included 22 of 193 patients from the 0.03% tacrolimus group, 22 of 191 patients from the 0.1% tacrolimus group, and 17 of 186 patients from the hydrocortisone butyrate group. The median mEASI mean area under the curve as a percentage of baseline was 47.0%, 36.5%, and 36.1% for patients who received 0.03% tacrolimus, 0.1% tacrolimus, and 0.1% hydrocortisone butyrate, respectively. There was no statistically significant difference between 0.1% tacrolimus and 0.1% hydrocortisone butyrate; however, the lower improvement in mEASI for 0.03% tacrolimus was statistically significant when compared with 0.1% tacrolimus (P <.001) or hydrocortisone butyrate (P =.002). Skin burning and pruritus at the application site showed a higher incidence in the tacrolimus treatment groups than in the hydrocortisone butyrate group (P <.05). Laboratory parameters showed no treatment differences and no marked changes over time.

CONCLUSIONS

The efficacy of 0.1% tacrolimus ointment was similar to that of 0.1% hydrocortisone butyrate ointment and was lower for 0.03% tacrolimus ointment. No serious safety concerns were identified.

The effect of recombinant rat interferon-gamma (rIFN-gamma) on acute disseminated Candida albicans infection in mice was investigated. Outgrowth of C. albicans in kidneys, spleen, and liver of mice treated with one intravenous (iv) dose of rIFN-gamma before iv injection of 5 x 10(5) cfu of C. albicans was significantly lower than in controls over 7 days. rIFN-gamma was protective when given 1 day before, simultaneously with, or 1-3 days after infection but not when given 3 days before. In mice pretreated with hydrocortisone acetate, rIFN-gamma significantly reduced the outgrowth only when 10(3) cfu of C. albicans was injected. Injection of rIFN-gamma did not reduce the outgrowth of C. albicans in cyclophosphamide-pretreated mice and significantly increased the capacity of peripheral blood and exudate peritoneal granulocytes to kill C. albicans in vitro. Thus, rIFN-gamma enhances host resistance against acute disseminated C. albicans infection in mice through activation of polymorphonuclear leukocytes.

Glucocorticoid hormones increase the level of hepatic tryptophan oxygenase (EC 1.13.11.11; L-tryptophan:oxygen 2,3-oxidoreductase (decyclizing) by increasing its rate of synthesis. Studies were performed to determine whether this induction is mediated by controlling the level of the mRNA for tryptophan oxygenase of by changing the translational efficiency of a fixed level of mRNA. Activity of tryptophan oxygenase mRNA was quantitated in a Krebs ascites cell-free, protein-synthesizing system, supplemented with tRNA and rabbit reticulocyte initiation factors. De novo synthesis of the protomeric unit(s) of the enzyme was a linear function of the amount of mRNA added. Time course and dose-response studies in which the enzyme level and mRNA activity in livers from rats injected with inducing doses of hydrocortisone were compared indicate that the induction of this enzyme is accompanied by a proportional increase in the level of its mRNA. This was true for mRNA isolated from total liver as well as from cytoplasmic polysomes. Induction of the enzyme by its substrate, tryptophan, however, was not accompanied by a parallel increase in mRNA activity.

Glucocorticoids inhibit the migration of neutrophils induced by endotoxin (E. coli lipopolysaccharide, LPS) in vivo. Macrophage monolayers stimulated by LPS showed a dose-dependent release into the supernatant of a chemotactic factor for neutrophils, MNCF, which was active in vivo and in vitro. Dexamethasone reduced the neutrophil migration into the abdominal cavities of rats that was induced by LPS, but did not affect the migration induced by MNCF. The release of MNCF by LPS-pretreated macrophage monolayers was inhibited by dexamethasone and hydrocortisone but not by indomethacin and BW755C. MNCF was stable at 56 degrees C and did not release histamine from mast cells. Thus, MNCF activity seems not to be due to arachidonic acid metabolites or C5/C5a. MNCF shares some properties with interleukin-I, such as the blockade of its release by glucocorticoids, the association of its activity with a material of a molecular weight greater than 10 000 Daltons and the abolition of its activity by incubation with phenylglyoxal. However MNCF liberation was not blocked by cycloheximide and the time course of its release by macrophage monolayers stimulated by LPS differed from that described for interleukin-1. In addition human interleukin-1 when tested in dexamethasone-treated test rats failed to induce neutrophil migration. It is suggested that inhibition by glucocorticoids of LPS-induced neutrophil migration in vivo is not due to a direct effect upon the migrating cells but rather to an indirect one, i.e. through blockade of MNCF release by macrophages.

OBJECTIVE

Patients with von Hippel-Lindau disease are predisposed to multiple bilateral adrenal pheochromocytoma. In these patients partial adrenalectomy may preserve adrenocortical function and avoid the morbidity associated with medical adrenal replacement. We report our experience with such cases.

METHODS

Laparoscopic partial adrenalectomy was performed in patients with von Hippel-Lindau disease and pheochromocytoma when there was evidence of normal adrenocortical tissue on preoperative imaging or intraoperative examination. Suture ligature or a harmonic scalpel was used to excise the tumors, leaving a 2 to 3 mm. margin of normal tissue.

RESULTS

Two patients underwent laparoscopic partial adrenalectomy and 1 laparoscopic bilateral partial adrenalectomy with preservation of normal adrenocortical tissue. Seven pheochromocytomas were removed. Laparoscopic ultrasound was essential for localizing 2 pheochromocytomas that were not visualized by the camera. Median operative time was 324 minutes, blood loss 100 cc and parenteral narcotic requirement 22 mg. morphine equivalents. No patient required hydrocortisone replacement. There has been no pheochromocytoma recurrence during short-term followup.

CONCLUSIONS

Laparoscopic partial adrenalectomy is technically feasible in patients with a hereditary form of pheochromocytoma, and may preserve adrenocortical function. Laparoscopic ultrasound was necessary to identify 2 of the 7 pheochromocytomas removed.

Human cytomegalovirus (HCMV) reactivation from latency causes disease in individuals who are immunocompromised or immunosuppressed. Activation of the major immediate-early (MIE) promoter is thought to be an initial step for reactivation. We determined whether expression of the MIE gene products in trans was sufficient to circumvent an HCMV latent-like state in an undifferentiated transformed human promonocytic (THP)-1 cell model system. Expression of the functional MIE proteins was achieved with a replication-defective adenovirus vector, Ad-IE1/2, which contains the MIE gene locus. Expression of the MIE proteins by Ad-IE1/2 prior to HCMV infection induced viral early gene expression accompanied by an increase in active chromatin signals. Expression of the anti-apoptotic protein encoded by UL37x1 increased viral early gene expression. However, viral DNA replication and production of infectious virus was not detected. As expected, cellular differentiation with phorbol 12-myristate 13-acetate and hydrocortisone induced virus production. Cellular differentiation is required for efficient viral reactivation.

BACKGROUND

Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis.

OBJECTIVE

Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH.

METHODS

This was a cross-sectional observational study.

METHODS

Tertiary care referral centers were used in this study.

METHODS

We studied 61 women, aged 18-63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls.

METHODS

History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, beta-C telopeptide was studied.

RESULTS

The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 +/- 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. beta-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058).

CONCLUSIONS

Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.

The mouse ear edema model is recognized for its usefulness in studying skin responses and damage following exposure to chemical irritants, and for evaluating pharmacological agents against chemically induced skin injury. We recently modified the mouse ear edema model for use with sulfur mustard (HD) and used this model to study the protective effect of 33 topically applied compounds comprising five pharmaceutical strategies (anti-inflammatories, protease inhibitors, scavengers/chelators, poly(ADP-ribose) polymerase (PARP) inhibitors, calcium modulators/chelators) against HD-induced dermatotoxicity. Pharmacological modulation of HD injury in mouse ears was established by a reduction in edema or histopathology (epidermal necrosis and epidermal-dermal separation) at 24 h following topical liquid HD exposure. Ten of the 33 compounds administered as single topical pretreatments up to 2 h prior to HD challenge produced significant reductions in edema. Five of these ten also produced significant reductions in histological endpoints. Three candidates (olvanil, indomethacin, hydrocortisone) showing protection at 24 h were evaluated further for 'extended protection' at 48 and 72 h after HD challenge and showed significant modulation of edema at 48 h but not at 72 h. Olvanil also showed significant reductions in histology at 48 and 72 h. Olvanil and indomethacin were shown to reduce significantly the edema at 24 h post-exposure when administered topically 10 min after HD challenge, with olvanil additionally protecting against epidermal necrosis. These results demonstrate prophylactic and treatment effects of pharmacological agents against HD-induced skin injury in an in vivo model and support the continued use of the mouse ear vesicant model (MEVM) for evaluating medical countermeasures against HD.

The ability of a single large intravenous dose of the sodium succinate esters of the glucocorticoids methylprednisolone, prednisolone, or hydrocortisone to enhance early neurological recovery after moderate to severe blunt head injury was examined in male CF-1 mice. Unanesthetized mice were restrained and subjected to a 900 gm-cm head injury produced by a 50-gm weight dropped 18 cm. This injury resulted in immediate loss of consciousness (loss of the righting reflex) in all animals, and death in approximately 30%. Survivors received a 0.1-ml tail vein injection of either vehicle or 15, 30, 60, or 120 mg/kg of methylprednisolone, prednisolone, or hydrocortisone within 5 minutes. Their neurological status was evaluated at 1 hour after injury. A 30-mg/kg dose of methylprednisolone was found to improve recovery significantly in comparison to that seen in vehicle-treated mice. A 15-mg/kg dose was less effective, and a 60- or 120-mg/kg dose was essentially ineffective. Prednisolone was also observed to improve neurological scores at 1 hour postinjury. A 60-mg/kg dose of prednisolone was optimal, while lower and higher doses had no effect. Hydrocortisone was unable to improve recovery over the wide dose range tested. The implications of these findings for the clinical management of head injury with glucocorticoid steroids are discussed.

BACKGROUND

Because of the disability associated with surgery for anal fissure and the risk of incontinence, medical alternatives for surgery have been sought. Most recently, pharmacologic methods that relax the anal smooth muscle, to accomplish reversibly what occurs in surgery, have been used to obtain fissure healing.

OBJECTIVE

To assess the efficacy and morbidity of various medical therapies for anal fissure.

METHODS

Search terms include "anal fissure randomized". Timing from 1966 to May 2006. Further details of the search below.

METHODS

Studies in which participants were randomized to a non-surgical therapy for anal fissure. Comparison groups may include an operative procedure, an alternate medical therapy or placebo. Chronic fissure, acute fissure and fissure in children are included in the review. Atypical fissures associated with inflammatory bowel disease or cancer or anal infection are excluded.

METHODS

Data were abstracted from published reports and meeting abstracts, assessing method of randomization, blinding, "intention to treat" and drop-outs, therapies, supportive measures (applied to both groups), dosing and frequency and cross-overs. Dichotomous outcome measures included Non-healing of the fissure (a combination of persistence and recurrence), and Adverse events (including incontinence, headache, infection, anaphylaxis). Continuous outcome measures included measures of pain relief and anorectal manometry.

RESULTS

48 different comparisons of the ability of medical therapies to heal anal fissure have been reported in 53 RCTs. Eleven agents were used (nitroglycerin ointment (GTN), isosorbide dinitrate, Botulinum toxin (Botox), diltiazem, nifedipine (Calcium channel blockers or CCBs), hydrocortisone, lignocaine, bran, minoxidil, indoramin, and placebo) as well as anal dilators and surgical sphincterotomy.GTN was found to be marginally but significantly better than placebo in healing anal fissure (48.6% vs. 37%, p < 0.004), but late recurrence of fissure was common, in the range of 50% of those initially cured. Botox and CCBs were equivalent to GTN in efficacy with fewer adverse events. No medical therapy came close to the efficacy of surgical sphincterotomy, though none in these RCTs was associated with the risk of incontinence.

CONCLUSIONS

Medical therapy for chronic anal fissure, acute fissure and fissure in children may be applied with a chance of cure that is marginally better than placebo, and, for chronic fissure in adults, far less effective than surgery.

Patients with critical illness who are treated in an intensive care unit (ICU) often report traumatic memories from ICU treatment, receive exogenously administered glucocorticoids for medical reasons, and have a relatively high incidence of chronic stress symptoms and posttraumatic stress disorder (PTSD) during follow-up. ICU therapy could therefore represent a useful model for investigating glucocorticoid effects on traumatic memories and PTSD development. Studies in long-term survivors of ICU treatment demonstrated a clear and vivid recall of different categories of traumatic memory such as nightmares, anxiety, respiratory distress, or pain. The incidence and intensity of PTSD symptoms increased with the number of categories of traumatic memory present. The prolonged administration of glucocorticoids (stress doses of hydrocortisone) to critically ill patients resulted in a significant reduction of PTSD symptoms measured after recovery without influencing the number of categories of traumatic memory. This protective effect of cortisol can possibly be explained by a cortisol-induced temporary impairment in traumatic memory retrieval which has previously been demonstrated in both rats and humans. Therefore, stress doses of hydrocortisone could be useful for prophylaxis and treatment of PTSD.

There is evidence that downregulation and desensitization of airway beta 2-adrenoceptors (beta 2-AR) develops after continuous exposure to long-acting beta 2-agonists such as formoterol and salmeterol. To investigate the facilitatory effects of acute administration of systemic corticosteroid on bronchodilator subsensitivity, as might occur in the setting of acute asthma, 12 subjects with moderately severe asthma, with a mean FEV1 of 66% predicted, of whom were all receiving inhaled corticosteriod, were randomized to receive either inhaled placebo (PL) or inhaled formoterol (FM) 24 micrograms twice daily for 4 wk in a double-blind crossover study. Subjects were also genotyped in terms of beta 2-Ar polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 108 micrograms) was produced 1 h after administration of placebo tablets and after injection at 3 wk, and 1 h after administration of oral prednisolone, 50 mg, and intravenous hydrocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for delta FEV1 (as AUC, L.h): 2.51 versus 4.22 (95% CI: 0.54 to 2.89; p = 0.01) and delta FEF25-75 (as AUC, L x 10(3)): 11.30 versus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly reversed by steroid (S) for FEV1 (FM versus FM+5): 2.51 versus 3.57 (95% CI: 0.11 to 2.27; p = 0.03) and for FEF25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte beta 2-AR density (log Bmax; fmol/10(6) cells) showed significant upregulation 3 h after steroid (FM+5 versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivity with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.001), and this was reversed by steroid (FM+5 versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic corticosteroid appears to be generally independent of beta 2-AR polymorphism at loci 16 and 27. In conclusion, we have demonstrated that bronchodilator subsensitivity occurs after regular inhaled FM in asthmatic patients, and is rapidly reversed by systemic corticosteroid. Thus, in acute asthma, systemic corticosteroid should be administered a soon as possible, in order to restore normal airway beta 2-AR sensitivity, particularly in patients who are receiving regular long-acting beta 2-agonists.

There is increasing evidence for an additional acute, nongenomic action of the mineralocorticoid hormone aldosterone on renal epithelial cells, leading to a two-step model of mineralocorticoid action on electrolyte excretion. We investigated the acute effect of aldosterone on intracellular free Ca2+ and on intracellular pH in an aldosterone-sensitive Madin-Darby canine kidney cell clone. Within seconds of application of aldosterone, but not of the glucocorticoid hydrocortisone, there was a 3-fold sustained increase of intracellular Ca2+ at a half-maximal concentration of 10(-10) mol/liter. Omission of extracellular Ca2+ prevented this hormone response. In the presence of extracellular Ca2+ aldosterone led to intracellular alkalinization. The Na+/H+ exchange inhibitor ethyl-isopropanol-amiloride (EIPA) prevented the aldosterone-induced alkalinization but not the aldosterone-induced increase of intracellular Ca2+. Omission of extracellular Ca2+ also prevented aldosterone-induced alkalinization. Instead, aldosterone led to a Zn(2+)-dependent intracellular acidification in the presence of EIPA, indicative of an increase of plasma membrane proton conductance. Under control conditions, Zn2+ prevented the aldosterone-induced alkalinization completely. We conclude that aldosterone stimulated net-entry of Ca2+ from the extracellular compartment and a plasma membrane H+ conductance as prerequisites for the stimulation of plasma membrane Na+/H+ exchange which in turn modulates K+ channel acitivity. It is probable that the aldosterone-sensitive H+ conductance maintains Na+/H+ exchange activity by providing an acidic environment in the vicinity of the exchanger. Thus, genomic action of aldosterone determines cellular transport equipment, whereas the nongenomic action regulates transporter activity that requires responses within seconds or minutes, which explains the rapid effects on electrolyte excretion.